PHOSMET JMPR 1978
Explanation
This compound was evaluated by the 1976 Meeting (FAO/WHO,
1977b) but no acceptable daily intake could be allocated in the
absence of the required full toxicological data. Although available
residue data were sufficient to allow some guideline levels to be
recorded, more detailed data from supervised trials on fruit and
forage crops were requested. The data received in response to these
requests are reviewed in this monograph addendum.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
BIOCHEMICAL ASPECTS
Absorption, distribution and excretion
Phosmet is rapidly absorbed, translocated and excreted in
mammals. Following a single oral administration of 14C
(Carbonyl-labelled) phosmet to rats at doses ranging from 23 to 35
mg/kg body weight, phosmet was eliminated rapidly (within 48 hours)
via the urine, greater than 75%) and feces (Ca 16%). Tissue
residues accounted for a very small portion (less than 3%) of the
Phosmet administered. The radiolabelled residue was fairly
uniformly distributed among many tissues. The gonads and fat
contained exceptionally low levels. Essentially no cleavage of the
carbonyl carbon of the phthalimide, group occurred as no 14CO2 was
observed. These data suggested the rapid absorption, distribution
and elimination of phosmet in mammals (Ford et al., 1966)
Phosmet was administered orally or by direct intra-amnionic
injection to rats in the final stages of pregnancy. Phosmet was
detected in fetuses following oral administration and in fetuses in
the uterine horn opposite of the site of intra-amnionic injection.
These studies readily demonstrated the rapid absorption as well as
the placental passage of phosmet (Ackermann et al., 1976).
Biotransformation
Following oral administration of phosmet to pregnant rats and
following injection directly into the fetus, metabolic (primarily
hydrolytic) products were rapidly noted. These products, small
amounts of the oxygen analog and the hydrolytic derivatives were
observed and were further degraded. Phosmet was also rapidly
metabolized in the fetus following direct injection into the fetus.
Thus, fetal tissues have the capacity to rapidly metabolize phosmet
which may pass the placental barrier during latter stages of
pregnancy (Ackermann et al., 1976). In further characterization of
the metabolites, the presence of phthalimide was noted which was
further observed to breakdown to phthalic acid. All of these
metabolites ware proposed for fetal tissue metabolism (Ackermann et
al., 1978).
Examination of urine and faces of rats treated with phosmet
(oral administration, 27 mg/kg body weight) suggested that
metabolic breakdown in vivo occurred primarily via hydrolytic
pathways and is believed to resemble degradation products from many
other organophosphorus pesticides. The major phosmet metabolite,
identified in urine of both sexes, was phthalamic acid. Phthalic
acid and a small number of unidentified minor metabolites.
Oxidative conversion, in vitro, of phosmet to its oxygen analog
was shown to occur in the presence of an active microsomal
oxidation system (McBain et al., 1968). In cotton plants, following
surface application to leaves, the major metabolites of phosmet
were found again to be phthalic and/or phthalamic acid, benzoic
acid and possibly some benzoic acid derivatives. It was suggested
that oxidation in the plant to the active oxygen analog was
bypassed in favor of hydrolysis as the oxygen was not found in
plant extracts (Menn and McBain, 1964).
Acute Toxicity
Following acute intoxication with phosmet the typical
parasympathomimetic signs of poisoning, generally seen with other
anticholinesterase agents, were observed. The onset of signs of
poisoning was rapid, generally within the first one-half hour after
treatment and included: tremors, salivation, lacrimation,
mastication, exophthalmia, bloody exudate from eyes, nose and
mouth, dyspnea, diarrhea, convulsions and death. The sings of
poisoning were transient, generally disappearing rapidly within 24
to 72 hours. On gross examination of animals acutely poisoned by
gavage treatment, congested lungs and adrenals, discoloration of
liver, spleen and kidney and distention and irritation of the GI
tract were observed.
Phosmet (3 mg technical) active ingredient or 0.1 ml of a 3EV
emulsifiable concentrate formulation instilled into the
conjunctival sac of rabbits was found to be irritating. The rabbits
displayed erythema of the eyelid, vacularization of the sclera and
nictitating membrane and lacrimation. The crystalline phosmet did
not dissolve readily. The signs of irritation induced by the
technical phosmet were transient, disappearing within 24 hours
after treatment. The irritation induced by the formulation lasted
longer than 7 days (Meyding, 1960; Meyding and Fogleman, 1962).
Acute one hour inhalation exposure of male rats to an aqueous
emulsion of phosmet at concentrations ranging from 50 to 800 ml/L
air resulted in changes in behavior and signs of poisoning ranging
from mild tremors and face washing to extreme tremors and distress.
Mortality was not noted. Gross examination after a 14 day rest and
recovery interval revealed lung, adrenal and pancreatic changes.
The lungs were brightly colored (orange red) and the adrenals and
pancreas were engorged or hemorrhagic (Hill, 1963).
The results of acute toxicity studies are summarized in Table
1.
TOXICOLOGICAL STUDIES
Acute Toxicity
LD50
Species Sex Route Solvent1 (mg/kg) 95% C.L. References
Rat M Oral Me Cell 147 Fogleman, 1960
Oral CO 140 76-235 Ford & Fogleman, 1962
Oral Me Cell 220 180-268 Ford & Fogleman, 1962
Oral Me Cell 245 161-367 Meyding, 1963
Oral Me Cell 242 192-305 Meyding, 1963
Oral Me Cell 304 261-356 Meyding, 1963
Oral Me Cell 310 267-360 Ray, 1064
F Oral PEG 271 200-369 Johnston, 1963a
oral PEG 369 271-501 Johnston, 1963a
oral PEG 316 Johnston, 1963a
oral PEG 224 176-286 Johnston, 1963a
M IP Me Cell 100 Meyding, 1965a
SC Me Cell 1200 Meyding, 1965a
Mouse M Oral Me Cell 50.1 34.4-73.0 Meyding, 1965a
M oral Polysorbate 80 25.2 22.9-27.7 Haley et al., 1975
F Oral Polysorbate 80 23.1 22.2-24.0 Haley et al., 1975
M IP Me Cell 40-50 Meyding, 1965a
M SC Me Cell 300 Meyding, 1965a
Rabbit M&F Dermal CO 3160 Meyding, 1960
(intact skin)
LD50
Species Sex Route Solvent1 (mg/kg) 95% C.L. References
Emulsifiable Concentrate
Rat M Oral Socal #2 623 Ray, 1963a
M Oral Water 501 344-730 Ray, 1963b
Water 316 Meyding, 1965b
Water 596 409-868 Meyding, 1965b
Mice M Oral Water 96 79-116 Ray, 1963b
Rabbit M&F Dermal None 1560 633-2220 Meyding & Fogleman, 1962
Wettable Powder
Rat M Oral Water 223 143-378 Anonymous, 1963
Mice M Oral Water 108 74-157 Anonymous, 1963
Rat M Oral Water 275 245-308 Bullock & Kamienski, 1972
Rat F Oral Water 258 239-289 Bullock & Kamienski, 1972
Rabbit - Dermal Neat 4640
1Me Cell = Aqueous Methyl Cellulose CO = Corn Oil PEG = Polyethylene Glycol 300
Special studies
Hen - Delayed Neurotoxicity
Groups of white leghorn hens (10 hens per treatment group, 3 hens
were used as a negative control) were fed dietary levels of phosmet at
dose levels of 0, 100, 316 and 1000 ppm over a six week period. A
positive control group was fed tri-o-cresyl phosphate (TOCP) at a
dietary level of 1000 ppm over the same time interval. At the
conclusion of the study surviving hens were sacrificed and
histological examinations of the spinal cord, brain and sciatic nerve
were performed following H&E staining of these tissues. A delayed
neurotoxic response was not observed either clinically of
histologically over the course of the study as a result of the
presence of phosmet in the diet. The presence of TOCP in the diet
resulted in ataxia and paralysis. Both clinical and histological
examinations confirmed this event. Based upon this dietary study it
was concluded that there was no delayed neurotoxic potential for
phosmet (Johnston, 1963b).
Potentiation
Technical phosmet was tested alone and in combination with
seventeen anticholinesterase insecticides (one carbamate and sixteen
organophosphate esters) in an effort to evaluate its additive or
potentiating effect. Groups of rats (5 females rats/group) were used
to evaluate the potentiation. Mortality ratios were calculated from
the toxicity of phosmet administered alone or in combination with
another anticholinesterase agent at one-half or one-fourth of the
respective LD50 value. Greater than additive mortality was observed
with several other compounds when dose levels of one-half of the acute
LD50 level were employed. However, when the dose level was reduced to
one quarter of the LD50 potentiation was observed only with one
organophosphate, fenchlorphos (Ronnel). The potentiation effect with
fenchlorfos was, however, questionable because of possible
interference from solvent effects (Johnston, 1963a).
Mutagenesis
Phosmet was tested for mutagenicity using a series of in vitro
microbial assays. At levels up to 20 micrograms dissolved in DMSO,
without metabolic activation, phosmet was inactive when tested against
B. subtillis (H17 - Rec + and M45 - Reco-): E. coli B/r WP2hr+
and WP2hcr-, 2 tryptophan- requiring mutants and S. typhimurium
(TA 1535, TA 1536, TA 1537 and TA 1538) (Shirasu, 1975, Shirasu et al,
1976).
Teratology
Rats
Groups of CD rats (group size varied from 9 to 32
individuals/group) were either administered phosmet in the diet at
concentrations yielding daily doses of 0, 10, 20, 27 and 29 mg/kg body
weight or by gavage at doses of 0, 5, 10, 20, 25 and 30 mg/kg body
weight from day 6-15 of gestation. Day 1 of gestation was the day
semen was detected. The unusual dosage levels of the dietary treatment
were a result of food rejection and correspond to actual intake of
phosmet calculated from diet consumption data. On day 21 of gestation,
the rats were sacrificed and fetuses examined for external and
internal malformations. Maternal toxicity was evident in the two
highest dietary levels. Food consumption was decreased and no weight
gain was recorded at these two levels. There was no indication of
fetal toxicity as measured by mortality, fetal weight or an overall
incidence of malformation. Maternal mortality was evident at the two
upper dose levels administered by gavages Against the incidence of
fetal mortality and malformation was not significantly increased even
in the presence of severely adverse maternal effects. There was no
evidence of somatic or skeletal abnormalities in the pups attributable
to the administration of phosmet (Staples et al., 1976).
Groups of wistar rats (group size varied from 9 to 13 pregnant
females/group) were administered phosmet orally by gavage at a single
dose of 30 mg/kg (9 females) on day 9 of gestation; at a single dose
of 30 mg/kg (8 females per dose) on day 13 of gestation; at doses of
0.06 or 1.5 mg/kg body weight (10 females/group) every other day
throughout pregnancy. Day 1 of gestation was the day semen was
detected. Suitable groups of controls varying from 10 to 13 animals
per group were used to compare results (it was not indicated whether
controls were administered solvent (not specified) or were not
treated). Administration of phosmet on day 9 of pregnancy resulted in
an insignificant increase in post implantation mortality of embryos
and malformations described as hypognathia, edema and dislocation of
extremities. Administration on day 13 of pregnancy did not affect
mortality but did induce hydrocephaly in 33 of 55 embryos examined.
Administration of phosmet (1.5 mg/kg bw every other day throughout
pregnancy) resulted in a reduction in the number of live fetuses and
the occurrence of hydrocephaly and subcutaneous hemmorhages. Embryo
toxicity was a dose-dependent occurrence as it was not noted at the
lowest concentration (0.06 mg/kg body weight) examined (Martson and
Voronina, 1976).
Monkey
Groups of rhesus monkeys (Macaca mulatta, 7 pregnant females
per group) were administered phosmet by gavage from days 22 through 32
of gestation at dose levels of 2, 4 and 8 mg/kg/ day. The females had
previously borne normal young and served as their own controls in the
study. A positive control was included utilizing various dose levels
of thalidomide (5 or 10 mg/kg/day) administered on days 22 through 32
of gestation or (10 mg/kg/day) administered an days 25, 26 and 27.
Malformations were observed in all fetuses delivered to females
administered 10 mg thalidomide kg/day during days 25-27 of gestation.
Administration of thalidomide from days 22-32 of gestation resulted in
abortion of all parents with an exception being noted at the high
dosage level (10 mg/kg/day) where 2 of 4 fetuses conceived were
delivered. These fetuses were malformed. Over the entire course of
this study all fetuses delivered to parents treated with thalidomide
displayed various degrees of abnormality. In contrast, all fetuses
delivered to females treated with phosmet showed no abnormalities. Two
females at the low doses and one female at the high dose group aborted
during the course of this study, All other females delivered live
viable fetuses which were anatomically normal. There was no indication
of a teratogenic event as a result of administration of phosmet during
the sensitive period of organogenesis in the rhesus monkey (Courtney
and Finkelstein, 1968).
Rabbit
Groups of pregnant rabbits (5 rabbits/group) were orally
administered phosmet by gavage at levels of 0 or 35 mg/kg/day from day
7-12 of gestation. The day of mating was considered as day zero for
calculation of gestation. There were no differences observed in the
reproductive parameters (implantation, resorption, litter size, litter
weight) and abnormalities were not observed over the course of the
study. In contrast, a positive control using thalidomide administered
orally at a dose of 150 mg/kg during the same period of gestation
resulted in a significant number of malformed fetuses (Fabro et al.,
1965).
Reproduction
Rabbit
Groups of rabbits (10-12 males and 10-13 females/group) were
administered phosmet either in the diet or by dermal application for
three weeks prior to mating and thereafter for 18 consecutive days of
gestation. Rabbits subjected to dietary administration were fed dosage
levels of 0, 10, 30 and 60 mg/kg/day, 7 days per week. Rabbits
subjected to dermal application received a dose of 0, 10, 30 and 60
mg/kg/day 5 days per week for the same treatment interval. At the
conclusion of the study, day 29 of gestation, pups were delivered by
Caesarian section. Gross and microscopic examination of tissues and
organs of parental animals and gross and skeletal examinations of pups
were performed. Cholinesterase activity of females, performed during
the course of the study, was depressed confirming that exposure to
phosmet had occurred. Depression of cholinesterase was evident at all
dose levels in animals administered phosmet by both the dermal and
dietary route.
There was no mortality observed in the study attributable to
phosmet. A slight reduction in growth was observed at the highest dose
level in animals of both the oral and dermal treatments. Gross and
microscopic examination of tissues and organs of the parents showed no
effects of the administration of phosmet. Reproductive parameters were
not affected by phosmet and teratogenic events were not observed over
the course of this study. Dietary and dermal administration of phosmet
at dose levels of 60 mg/kg/body weight per day prior to and during
mating and over the entire period of gestation, did not affect
reproductive parameters in rabbits and induced no teratogenic event in
offspring (Kidwell et al., 1966).
Rat
Groups of rats (20 males and 20 females/group) were fed dietary
concentrations of phosmet and utilized in a standard three-generation,
two-litter generation, reproduction study. Two groups of rats were
used in the first generation and three groups were used for the second
and third generations. The first generation, consisting of two
complete litters, were fed dietary concentrations of 0 and 40 ppm.
Immediately after weaning the test material was withdrawn for 3-4
weeks. The second and third generations were fed dietary
concentrations of 0, 40 and 80 ppm, the latter group being derived
from offspring of parents previously fed 40 ppm in the diet. The first
litters of each generation were sacrificed at weaning and the second
litter was used as the parental group of the following generation. At
weaning of the accord litter the parental animals were discarded. A
2-9 day withdrawal period from the phosmet diet occurred immediately
after weaning. At the conclusion of the F3b offspring,
representatives of the second litter were grossly examined at necropsy
and histological examination of selected tissues and organs was made.
There were no differences in any of the test and control groups
with respect to mortality, survival, general condition, growth and
reproductive performance. Malformations were not observed over the
course of the study. Gross and microscopic examinations of tissues and
organs at the conclusion of the study showed some slight degenerative
hepatic changes in both groups fed phosmet in the diet. These changes
were believed to be minor and included slight hepatic cell vaculation
and reduced glycogen content. Based upon comparison of data from
corresponding phosmet-treated and control litters in the three
generation reproduction study, the administration of phosmet at 80 ppm
in the diet for two generations and 40 ppm in the diet over a single
generation (all generations producing two litters) resulted in no
effect or any reproductive parameter (Hollingeworth et al., 1965).
Short Term Studies
Rabbit
Groups of rabbits (2 males and 2 females per group) were
administered phosmet (an emulsifiable concentrate or wettable powder
formulation) dermally five days/week for three weeks. Phosmet was
administered to both normal and abraded skin at daily doses of 0,
0.08, 0.16, 0.8 and 1.6 mg/kg/body weight (this dosage of the
emulsifiable concentrate corresponds to a concentration of 0, 30, 60,
300 and 600 mg/kg/body weight) and 0, 0.1, 0.5 and 1.0 gms/kg body
weight (this dosage of the 50% wettable powder formulation corresponds
to a concentration of 0, 50, 250 and 500 mg/kg body weight).
Mortality was evident with the emulsifiable concentrate as all
animals dosed at 600 mg/kg died and three out of four animals treated
with 300 mg/kg also died within the first week. Animals dosed at the
two intermediate dose levels lost weight. No effects were seen at the
lowest dose level. Repeated application of the emulsifiable
concentrate produced thickening of the skin in the treated area
followed by a dry, scaly condition. Cholinesterase depression was
observed at all dosage levels and did not appear to be affected by
skin abrasion. Cholinesterase depression was noted at 60 mg/kg body
weight with the emulsifiable concentrate. Cholinesterase was not
depressed at 50 mg/kg body weight when the wettable powder formulation
was used. These data suggested differences in dermal absorption or
penetration patterns with the two formulated materials. Brain
cholinesterase evaluated at the conclusion of the study showed
significant depression only at 300 mg/kg with the emulsifiable
concentrate and at 50 mg/kg with the wettable powder formulation.
Gross and microscopic examination of tissues and organs with the
exception of dermal thickening, showed no changes attributable to
phosmet administration (Hill and Moulten, 1963).
Rabbit
Groups of rabbits (10 males and 10 females/group, 5 of each sex
were used as the controls) were dermally administered phosmet
(emulsifiable concentrate formulation, 3-E) at dose levels of 0, 30
and 60 mg/kg/day, 5 days a week for 3 consecutive weeks. Phosmet was
again administered to either intact or abraded skin.
Mortality was observed in the high dose group with all animals
dying within one week having been treated with from 2-4 applications.
In the surviving animals no overt signs of poisoning were observed at
the low dosage level. Food consumption and body weight was reduced.
Dermal irritation was evident with no differences noted in the intact
and abraded skin with respect to evaluating the degree of irritation.
Hematology and urinalysis determinations at the end of the study were
normal. Cholinesterase depression was observed particularly with red
blood cell and again no differences were observed in animals with
intact or abraded skin. Gross and microscopic examination of selected
tissues and organs showed no somatic response to the dermal treatment
(Meyding, et al., 1965).
In a repeat experiment, groups of male and female rabbits were
administered phosmet dermally to intact or abraded skin at dose levels
varying from 0 to 300 mg/kg/day, 5 days a week for 3 weeks. Again,
mortality was observed at the high dose level and overall results of
this experiment confirmed that reported previously. One additional
group was used to evaluate the inert ingredients of the emulsifiable
concentrate formulation. Irritation of the intact and abraded dermal
surface was noted with this formulation suggesting that skin
irritation vas a property of the formulation rather than of the active
ingredient (Meyding and Horton, 1965).
Cattle
Groups of steers (15 hereford steers/group) were fed phosmet
(ProlateR, as a 50% wettable powder) in the diet at concentrations
of 0 and 1 mg/kg for 8 weeks end thereafter at levels of 0 and 2 mg/kg
for an additional 8-week period. There were no adverse effects on
behavior, growth and hematological parameters. Whole blood
cholinesterase depression was observed at the 2 mg/kg group after 6
weeks of dietary administration. Regeneration of cholinesterase was
slow over a 4-week control diet treatment after the 16 week trial
(Meyding, 1965c).
Rat
Two groups of rats (10 males and 10 females per group) were fed
varying dietary levels of phosmet over a sixteen week range-finding
study. A third group of rats consisting of 10 males and 10 females
were designated as controls and fed diets containing no phosmet for
the same sixteen week interval. A high level group was fed 800 ppm for
three weeks, 1600 ppm for weeks 4-9, 2000 ppm during the tenth week,
3000 ppm during the eleventh week and 6000 ppm from the 12-16 weeks.
The low level group was fed 450 ppm for the first three weeks, 900 ppm
for weeks 4-9 and 1120 ppm the tenth week and thereafter until the
conclusion of the study. Mortality was observed in the high dietary
level group where two females died at the sixteenth week.
Abnormalities in behavior were observed after the third week where all
treated animals appeared to develop a degree of hyperexcitability. By
the fourth week, tremors were noted which continued throughout the
remainder of the study. Persistent low grade diarrhea occurred in all
test animals after the 5th or 6th week. Growth was slightly depressed
at fifteen weeks in the low group and was more significantly depressed
in the high dose group. Growth depression was associated with
decreased food intake after the eight week. Hematological values were
normal in all groups. Cholinesterase depression was observed in red
blood cell and brain in both groups while plasma cholinesterase was
only partially depressed. Gross and microscopic pathological changes
were observed. Mean organ weights were increased in the high level.
This occurred in liver, kidney, spleen and adrenal gland. In addition,
testes weight was increased in both treatment groups. There were some
additional gross events noted in the low level group. Histologically,
hepatic degenerative changes were noted particularly in the high
level. To a lesser degree these changes were observed in the low level
animals. Adrenal hypertrophy use also reported. In this range finding
study it was observed that high levels of phosmet in the diet resulted
in significant toxicological effects (Johnston, 1963c).
Rat
Groups of rats (30 males and 30 females per group) were fed
phosmet in the diet at concentrations of 0, 20, 100 and 500 ppm for
periods varying from 19-24 weeks. The animals were fed a constant
dietary preparation over the course of this study. There was no
mortality attributable to the presence of phosmet in the diet. Growth,
as evidenced by weight gain, was reduced in males at 500 ppm. Females
were not affected. General appearance and behavior of all animals over
the course of the study was unaffected by the presence of phosmet.
Hematological evaluations made periodically over the course of the
study were within normal limits. Cholinesterase activity was depressed
at the dietary levels of 100 ppm and above. Red blood cell
cholinesterase was significantly more depressed than was plasma. Brain
cholinesterase, examined in a selected group of animals at thirteen
weeks, was found to be depressed in a manner similar to that observed
with cholinesterase from red blood cells. Gross and microscopic
examination of tissues and organs, performed on a small group of
animals sacrificed at fourteen weeks, showed no outstanding
abnormalities attributable to the presence of phosmet in the diet.
Based upon cholinesterase depression observed at 100 ppm, 20 ppm
phosmet in the diet was considered to be a no-effect level (Johnston,
1962).
Dog
Groups of beagle dogs (4 males and 4 females per group) were fed
dietary concentrations of phosmet at dosage levels of 0, 10, 75 and
563 ppm. Growth and behavior over the course of the study were
unaffected by the presence of phosmet in the diet. Hematological and
blood chemistry determinations were made periodically during the
course of the 20 week study. With the exception of blood
cholinesterase activity, all values were normal. Plasma and red blood
cholinesterase (and brain cholinesterase at the conclusion of the
study) were significantly inhibited by 563 ppm phosmet in the diet. At
75 ppm in the diet the red blood cell was slightly depressed in
females. Plasma cholinesterase activity was not depressed at this dose
level. Gross examination of tissues and organs performed at the
fourteen week interval showed a slightly increased kidney and adrenal
organ weight at the high dose level. Microscopic examination of
sections of tissues and organs suggested no cellular changes
attributable to the presence of phosmet in the diet (Johnston, 1962).
Dog - Two Year Study
Groups of purebred beagles (3 males and 3 females/group) were fed
dietary concentrations of phosmet for two years. Phosmet was mixed
with a dry diet at concentrations yielding 0, 20, 40 and 400 ppm. With
the exception of one dog, which was sacrificed in extremis at one year
of age, there was no mortality observed over the course of the study.
Growth, as evidenced by body weight changes, was unaffected.
Hematological values, clinical chemistry values, urinalysis values and
physical and physiological measurements taken at periodic intervals
and at the conclusion of the study showed no effects due to the
presence of phosmet in the diet. Transient physiological evidence of
the presence of an anticholinesterase agent in the diet was
sporadically reported as lacrimation and diarrhea noted in the treated
groups. Red blood cell, plasma and brain cholinesterase activity
(brain cholinesterase activity was recorded only at the conclusion of
the study) showed a distinct effect of phosmet at 400 ppm in the diet.
Depression of red blood cell and brain cholinesterase activity was
observed. Cholinesterase activity at 40 ppm in the diet was normal,
Neurological and ophthamological examinations performed at the
conclusion of the study were normal. Based upon cholinesterase
depression at 400 ppm in the diet, a no-effect level of 40 ppm was
observed in the study (Lobdell and Johnston, 1966).
Long Term Studies
Rat
Groups of Charles River rats (25 males and 25 females/group) were
fed dietary levels of phosmet for two years at dosage levels of 0, 20,
40 and 400 ppm (the animals were originally fed dietary levels of 0,
10, 20 and 200 ppm for three weeks after which time the dietary levels
was increased to compensate for differences in food intake). There was
no mortality nor behavioral differences in these animals that were
attributable to the presence of phosmet in the diet. Growth was
depressed at the dietary level of 400 ppm and was more readily
apparent in males. Food consumption was normal in all groups.
Hematological parameters, examined at various intervals over the
course of the study, were unaffected by phosmet in the diet. Plasma
and red blood cell cholinesterase activity evaluated at various time
intervals and brain cholinesterase, evaluated at the conclusion of the
study, were depressed at the highest dose levels at dietary levels of
40 ppm and below there were no effects on cholinesterase activity. In
addition, cholinesterase activity measured initially at 14 weeks, was
constant over the course of the study in each of the dietary groups.
Gross and microscopic examination of tissues and organs at the
conclusion of the study showed no consistent dose-related effects.
Histopathological changes noted were common in normal aging rats
although a degree of liver cell vaculation, observed 400 ppm, may have
been attributable to the presence of phosmet in the diet. There were
no differences with respect to neoplasms in the study although a
larger proportion of rats sacrificed at the conclusion of the study
having been fed 40 ppm phosmet and above showed the presence of
pituitary neoplasms. As the frequency of this event was significantly
small, no conclusion could be reached. In addition, thyroid adenomas
were observed at the 400 ppm group in greater frequency than were
noted in other dose groups. Again, the number of animals sacrificed at
the conclusion of the study was too small to fully evaluate this
parameter.
Based upon cholinesterase depression at 400 ppm, a proposed
no-effect level would be 40 ppm equivalent to 2 mg/kg/bw/day (Lobdell
and Johnston, 1966).
Observations in Man
No specific studies available. Limited observations of
occupationally exposed workers show no adverse effects although
depressed peripheral cholinesterase activity suggested that exposure
had occurred in some instances.
COMMENTS
The lipophilic nature of the phosmet molecule allows rapid
gastrointestinal absorption and dermal penetration but is not of such
a nature to suggest bioaccumulation in adipose tissue. Phosmet in
rapidly translocated in the body, metabolized and excreted. The
metabolic products in mammals and plants appear to be similar and are
well defined.
The acute toxicity of phosmet has been evaluated and data have
been presented to demonstrate its anticholinesterase activity and
parasympathomimetic properties. It is moderately toxic on an acute
basis.
Short term studies, in vitro bioassays for potential mutagenic
hazard and delayed neurotoxicity have been negative. Teratology
bioassays using a variety of species and protocols have, with one
exception, been negative. A teratological response in rat for phosmet
using a protocol not generally followed by other investigators, has
shown effects at exceptionally low levels. A no-effect level of 0.06
mg/kg noted in this teratology bioassay was of significant concern to
the Meeting. These teratology results served as a basis for applying
an unusually large safety margin to the allocated temporary ADI. In
another study in rat using high dose levels and a longer treatment
interval, data showed no teratological response. Negative results
obtained in the rat study and in a primate teratology bioassay did not
fully reduce the concern raised above with respect to the teratogenic
potential of phosmet.
Short term and long term bioassay programmes in dogs and rats
have shown no significant effects on a variety of physiological
biochemical and pathological parameters. As expected, a sensitive
indicator of effect, cholinesterase depression was observed at high
dietary levels in all tests. Growth depression and cholinesterase
activity depression in two species served as the basis for estimating
the no-effect level.
TOXICOLOGICAL EVALUATION
Level causing no significant toxicological effect in animals
Rat: 40 ppm in the diet equivalent to 2.0 mg/kg bw
Dog: 75 ppm in the diet equivalent to 1.9 mg/kg bw
Estimate of temporary acceptable daily intake for man
0 - 0.005 mg/kg body weight
RESIDUES IN FOOD AND THEIR EVALUATION
RESIDUES RESULTING FROM SUPERVISED TRIALS
Potatoes
Supervised trials of spray applications of phosmet to potatoes at
six sites in the USA and five sites in Canada in 1970 yielded only one
result (at 0.04 mg/kg) above the detection limit of 0.02 mg/kg for
either the parent compound or its oxygen analogue (Stauffer, 1970).
Sweet potatoes
Supervised trials of dust and dip treatments of stored sweet
potatoes yielded residues of phosmet which ranged up to 203 mg/kg.
Most results on unwashed tubers were in the range 50 to 100 mg/kg;
washing the tubers reduced the residue to between 2 and 10 mg/kg. The
bulk of the residue remains in the peel, levels in the edible pulp
being generally below 1 mg/kg (Stauffer, 1972).
Apples and pears
Additional data on residues in apples grown in Czechoslovakia
(Batora, 1978) have confirmed those reported by the 1976 Meeting,
observed levels ranging from 0.80 mg/kg just after treatment to 0.10
mg/kg 18 days later. Similar residues (0.85 to 0.11 mg/kg were
observed on pears.
Apricots and nectarines
Data on residues of phosmet on apricots and nectarines (Stauffer,
1968) showed that levels were similar to those reported in 1976 for
residues on peaches; they were below 5 mg/kg 7 days after treatment
and below 1 mg/kg after 21 days.
Grapes
Grapes treated with phosmet showed residues up to 15 mg/kg most
results lying in the range 1 to 8 mg/kg and showing limited diminution
with time up to 28 days after treatment (Stauffer, 1969).
Kiwifruit
Kiwifruit (Actinidia chinensis) is a major horticultural
product exported from New Zealand. Because of the hairy nature of its
skin, pesticide spray residues are retained to an appreciable extent.
Data reported by the 1976 Meeting showed that residues of phosmet
ranged up to 25 mg/kg, though most results were below 10 mg/kg.
Further recent information has shown that most of this residue (ca
90%) is associated with the inedible skin, levels in the fruit pulp
being in the range 0.3 to 2.5 mg/kg with a mean of 1 mg/kg (Love et
al., 1978). These data have been supported by monitoring studies,
results from 57 samples examined in 1975, 1977 and 1978 ranged up to
23 mg/kg with a mean value of 4 mg/kg (New Zealand, 1978).
Citrus fruit
Residues of phosmet on grapefruits, lemons and oranges, ranged
from 0.6 to 4 mg/kg at a pre-harvest interval of 7 or 8 days, most
being between 1 and 3 mg/kg. Studies on oranges and grapefruits showed
that nearly all of the residues in the peel, very little appearing in
the flesh or the juice. The proportion of the total residue occurring
as the oxygen analogue varied widely, from 1 to over 50% (Stauffer,
1974).
Maize (field corn)
On maize ears (i.e. kernels plus cob with husks removed) phosmet
residues were generally below 0.05 mg/kg but ranged up to 0.2 mg/kg;
residues in the stalks were appreciably higher, reaching 12 mg/kg
(Stauffer, 1974).
Nuts
Data were available on phosmet residues in almonds, filberts,
pecans and walnuts (Stauffer, 1974). Residues in the nut meat were all
below 0.08 mg/kg most being in the range 0.01 to 0.05 mg/kg. Residues
in almond hulls ranged up to 5.6 mg/kg.
Blueberries and cranberries
Phosmet residues on blueberries and cranberries showed a similar
pattern, ranging from 1 to 7 mg/kg at a 3-day pre-harvest interval
(Stauffer, 1974).
Peas
On peas plus pods, phosmet residues ranged from 0.07 to 0.34
mg/kg at a 7-day pre-harvest interval. Residues in dry peas were not
greater than 0.02 mg/kg (Stauffer, 1974).
NATIONAL MAXIMUM RESIDUE LIMITS
National MRLs reported to the Meeting are given in Table 2.
TABLE 2. National MRLs reported to the Meeting
Country Commodity MRL, mg/kg
Australia Fat of meat of cattle, pome
fruit, stone fruit 1
Milk and milk products
(fat basis) 0.2
Canada Apples, grapes, peaches, pears 10
Cherries 7
Plums 5
Netherlands Apples, pears 1
Potatoes 0.02
New Zealand Fruit 10
Switzerland Peas 0.1
Pome fruit 1
Potatoes 0.05
USA Alfalfa 40
Almond hulls, apples, blueberries.
cherries, corn forage and fodder
(including sweet corn, field corn
and popcorn), cranberries, grapes,
peaches, pears, pea forage and hay,
sweet potatoes (from post harvest
application). 10
Apricots, citrus fruits,
nectarines, plums. 5
Fresh corn including sweet
corn (kernels plus cobs with
husk removed), corn grain
(including popcorn), peas 0.5
Meat, fat and meat by-products of
cattle, goats, hogs, horses and
sheep 0.2
Potatoes 0.1
Nuts 0.1
(negligible
residues)
APPRAISAL
Some additional data have become available concerning residues of
phosmet in several crops. As the Meeting allocated a temporary ADI,
the previously recorded guideline levels were converted to temporary
maximum residue limits and some additional and amended limits were
also recommended.
RECOMMENDATIONS
The previously recorded guideline levels are replaced by the
following temporary maximum residue limits, which now refer to the sum
of phosmet and its oxygen analogue.
Commodity Temporary MRL, mg/kg Pre-harvest
intervals on which
limits are based,
days
Sweet potatoes (washed
before analysis) 10 -
Kiwifruit 10 10
Blueberries 10 3
Grapes 5 21
Forage crops (dry) 5 14
Citrus fruit 5 7
Cranberries 5 7
Apples 1 21
Apricots 1 21
Nectarines 1 21
Peaches 1 21
Pears 1 21
Fat of meat of cattle 1 -
Maize (kernels & cobs,
husks removed) 0.2 14
Commodity Temporary MRL, mg/kg Pre-harvest
intervals on which
limits are based,
days
Milk products
(fat basis) 0.2 -
Tree nuts (shelled) 0.1 -
Peas (fresh or dried) 0.1 7
Potatoes 0.05 20
Milk (whole) 0.01 -
FURTHER WORK OR INFORMATION
Required (on or before June 30, 1979)
1. Additional teratogenic studies in rodents.
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